1. ¹Faculty of Life Sciences, The University of Manchester, Stopford Building, Oxford Road, Manchester, UK
2. ²Department of Drug Research and Evaluation, Section of Cell Aging and Degeneration, Rome, Italy
3. ³Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
4. ⁴Department of Experimental Medicine and Pathology, Universita' 'La Sapienza', Rome, Italy
5. ⁵Technology and Health, Istituto Superiore Sanita', Rome, Italy

Correspondence: M Degli Esposti, Faculty of Life Sciences, The University of Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, UK. E-mail: mauro.esposti@manchester.ac.uk

⁶Equally senior authors.

Received 10 April 2006; Revised 9 August 2006; Accepted 10 August 2006; Published online 29 September 2006.

Abstract

Subcellular organelles such as mitochondria, endoplasmic reticulum (ER) and the Golgi complex are involved in the progression of the cell death programme. We report here that soon after ligation of Fas (CD95/Apo1) in type II cells, elements of the Golgi complex intermix with mitochondria. This mixing follows centrifugal dispersal of secretory membranes and reflects a global alteration of membrane traffic. Activation of apical caspases is instrumental for promoting the dispersal of secretory organelles, since caspase inhibition blocks the outward movement of Golgi-related endomembranes and reduces their mixing with mitochondria. Caspase inhibition also blocks the FasL-induced secretion of intracellular proteases from lysosomal compartments, outlining a novel aspect of death receptor signalling via apical caspases. Thus, our work unveils that Fas ligand-mediated apoptosis induces scrambling of mitochondrial and secretory organelles via a global alteration of membrane traffic that is modulated by apical caspases.